Sialic acid acetyl esterase (SIAE) is an enzyme that removes acetyl moieties from the 9-OH position of sialic acid on N-glycans, making available ligands for some inhibitory Siglecs, the best studied member of this family being Siglec-2/CD22. The loss of SIAE results in enhanced B cell receptor signaling and a break in tolerance. Defective rare variants of SIAE have been discovered in human autoimmune subjects. SIAE appears to be an important regulator of a pathway of clonal ignorance in B cells, and the mechanism by which this clonal ignorance is maintained will be studied using B cell receptor knockin and transgenic models. Studies are also proposed to examine why the absence of SIAE results in an increase in CD4+ effector memory phenotype T cells. This phenotype might be mediated by a defect in B cells or a defect in dendritic cells or both. Studies will be performed to determine the mechanism that leads to this enhanced accumulation of effector memory phenotype CD4+ T cells. The potential for the functional categorization of conventional and plasmacytoid dendritic cells based on the level of 9-O-acetylation of sialic acid will be explored and the phenotype of a mutant mouse lacking a putative 9-O-acetyl transferase will be examined. Studies are also proposed to examine whether disease-related heterozygous catalytically defective variants of SIAE are misfolded proteins and a knockin approach will be used to ask if one of these variants functions in a dominant negative fashion in vivo.